Abstract 1453: Evidence of divergent germline associations for breast cancer molecular subtype through distal-mediator enriched Transcriptome-Wide Association Study
Authors: Achal Patel, Melissa Troester, Bogdan Pasaniuc, Andrew Olshan, Michael Love, Arjun Bhattacharya
Journal: Cancer Research (2022)

Abstract Background: Of the 210 genetic variants identified for breast cancer (BC), many show differential associations across BC molecular subtype. Moreover, genes that underlie observed GWAS associations are often uncertain or unknown. We address this gap through a Transcriptome-Wide Association Study (TWAS), where we uncover potential genetic mechanisms (germline -&amp;gt; expression -&amp;gt; Subtype) for BC subtype at known and novel loci. Importantly, we incorporate both local and prioritized distal variants (MOSTWAS) across TWAS analyses, and leverage this feature of MOSTWAS for integrated discovery of tissue-specific genetic mechanisms across etiologically relevant (mammary breast, adipose, fibroblast, immune) tissues for BC. Methods: MOSTWAS predictive models of gene expression were constructed in etiologic tissue using GTEx v8 (all available matched genotype-expression samples), and integrated with GWAS summary statistics (N=101,820) for BC molecular subtypes. We considered genes TWAS-significant if they passed a global Bonferroni threshold of p = 2.2 x 10-7 (0.05/183,260 gene-tissue-subtype combinations) and an additional permutation test (FDR p &amp;lt;0.05) and gene mappability assessment. Results: Across etiologic tissue, we identified 293, 186, 201, 153, and 171 unique TWAS genes for Luminal A, Luminal B/HER2-, Luminal B, HER2, and Basal-like subtypes, respectively. Majority of these genes were identified at loci not uncovered in BC GWAS. Across subtypes, only 73, 46, 39, 32, and 38 genes, respectively, were identified in breast tissue, suggesting that germline-regulated gene expression in adipose, fibroblast, and immune tissue is also integral to risk of BC subtypes. The percentage of TWAS genes shared across 2 or more subtypes ranged from 29.7% for Luminal A to 38.6% for Basal. Moreover, among genes significant across more than one subtype for a given tissue, a sizable proportion (e.g., ~25% in Breast tissue) had discordant direction of associations. Together, these suggest divergent germline etiology for BC subtypes. We additionally identified genes such as CBX8 which confer increased risk for all subtypes, in line with CBX8’s documented role as an oncogene for breast and other carcinomas. Lastly, we observed that the proportion of TWAS genes with a significant distal component to the TWAS association was highest among adipose tissue (~30%). Validation of these distal components for identification of shared and tissue-specific upstream regulatory elements is underway. Conclusion: Our findings suggest divergent germline etiology for BC subtypes, and suggest that germline-regulated gene expression in tissues other than breast (i.e., adipose, fibroblast, immune) is also integral to risk of BC subtypes. Citation Format: Achal Patel, Melissa Troester, Bogdan Pasaniuc, Andrew Olshan, Michael Love, Arjun Bhattacharya. Evidence of divergent germline associations for breast cancer molecular subtype through distal-mediator enriched Transcriptome-Wide Association Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1453.